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NK cells sense tumors, course of disease and treatments: Consequences for NK-based therapies.

Fregni G, Perier A, Avril MF, Caignard A - Oncoimmunology (2012)

Bottom Line: The recent findings on NK activation indicate that these cells are important antitumor effectors.However, tumor-infiltrating NK cells are yet poorly characterized.We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin-INSERM U06; CNRS UMR 804; Université Paris Descartes; Paris, France.

ABSTRACT
The recent findings on NK activation indicate that these cells are important antitumor effectors. NK cells participate in the graft-vs.-leukemia effect to control the relapse in leukemic patients transplanted with allogeneic hematopoietic stem cells. In various tumors, correlation between NK cell infiltrates and prognosis were reported. However, tumor-infiltrating NK cells are yet poorly characterized. We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

No MeSH data available.


Related in: MedlinePlus

Figure 2. Tumors parameters implicated in the activation of NK cells. In RCC, VHL mutations induce constitutive activation and accumulation of Hypoxia-inducible factor (HIF). Certain VHL mutations correlate with low HLA-I molecules expression via a partially HIF-dependent pathway. The low expression of HLA-I molecules by VHL-mutated RCC cells reduces the engagement of NKG2A inhibitory receptor, shifting the balance toward NK cell activation. Membrane HLA-G molecules upregulate inhibitory receptors (NKG2A,and ILT2) on NK cells. Membrane-bound IL15 (Mb-IL15) is involved in NK cell activation and survival. In CML, the oncogeneic protein bcr/abl induces the expression of ICAM-1 and NKG2D ligands on myeloid cells favoring NK/target conjugates and lysis. Altered IFNγ signaling in bcr/abl target maintains a low HLA-I molecules expression. Bcr/abl dendritic cells activate NK cells via NKG2D receptor. Imatinib mesylate interferes with NK/leukemic targets.24 DC: Dendritic cell; IM: Imatinib Mesylate; IRF: Interferon regulatory factor; STAT-1: Signal Transducer and Activator of Transcription factor-1.
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Figure 2: Figure 2. Tumors parameters implicated in the activation of NK cells. In RCC, VHL mutations induce constitutive activation and accumulation of Hypoxia-inducible factor (HIF). Certain VHL mutations correlate with low HLA-I molecules expression via a partially HIF-dependent pathway. The low expression of HLA-I molecules by VHL-mutated RCC cells reduces the engagement of NKG2A inhibitory receptor, shifting the balance toward NK cell activation. Membrane HLA-G molecules upregulate inhibitory receptors (NKG2A,and ILT2) on NK cells. Membrane-bound IL15 (Mb-IL15) is involved in NK cell activation and survival. In CML, the oncogeneic protein bcr/abl induces the expression of ICAM-1 and NKG2D ligands on myeloid cells favoring NK/target conjugates and lysis. Altered IFNγ signaling in bcr/abl target maintains a low HLA-I molecules expression. Bcr/abl dendritic cells activate NK cells via NKG2D receptor. Imatinib mesylate interferes with NK/leukemic targets.24 DC: Dendritic cell; IM: Imatinib Mesylate; IRF: Interferon regulatory factor; STAT-1: Signal Transducer and Activator of Transcription factor-1.

Mentions: In RCC, we have shown that loss-of-function mutations of Von Hippel Lindau (VHL) gene may be targeted by NK cells (Fig. 2). This oncogenic event is important for the development of these tumors and 80% of RCC bear mutations in VHL gene leading to HIF (Hypoxia-inducible factor)-1 accumulation and increased activation of downstream signaling pathways.11,12 Previous studies including ours showed that NK cells lyse RCC cell lines and that LFA-1/ICAM-1 and HLA-I/NKR interactions are important in RCC recognition by NK cells.13-15 We have shown that certain loss-of-function VHL mutations correlate with a reduced expression of classical HLA-I molecules via a partially HIF-1α-dependent mechanism and with higher RCC lysis by NK cells.16 These results corroborate previous findings reporting that VHL controls the constitutive expression of STAT-1 and LMP2, involved in MHC-I dependent antigen presentation, probably via the downregulation of STRA-13.17 HLA-E molecules, ligands of the inhibitory receptor NKG2A, are also decreased in VHL-mutated cells. HLA-E promoter also contains STAT-1 binding site.18 HLA-I molecules are often downregulated in tumors and their modulation is considered a common mechanism of tumor escape from T cell immune response.19 Conversely, low HLA-I expression may shift the balance toward activation in NK cells. In non-tumor pathology and upon hypoxia-dependent HIF accumulation, the expression of MICA/B molecules, stress-induced ligands of the activating receptor NKG2D, was found augmented and correlated with increased NK cytotoxicity.20,21 In our studies, the expression of NKG2D ligands was not controlled by VHL mutation.


NK cells sense tumors, course of disease and treatments: Consequences for NK-based therapies.

Fregni G, Perier A, Avril MF, Caignard A - Oncoimmunology (2012)

Figure 2. Tumors parameters implicated in the activation of NK cells. In RCC, VHL mutations induce constitutive activation and accumulation of Hypoxia-inducible factor (HIF). Certain VHL mutations correlate with low HLA-I molecules expression via a partially HIF-dependent pathway. The low expression of HLA-I molecules by VHL-mutated RCC cells reduces the engagement of NKG2A inhibitory receptor, shifting the balance toward NK cell activation. Membrane HLA-G molecules upregulate inhibitory receptors (NKG2A,and ILT2) on NK cells. Membrane-bound IL15 (Mb-IL15) is involved in NK cell activation and survival. In CML, the oncogeneic protein bcr/abl induces the expression of ICAM-1 and NKG2D ligands on myeloid cells favoring NK/target conjugates and lysis. Altered IFNγ signaling in bcr/abl target maintains a low HLA-I molecules expression. Bcr/abl dendritic cells activate NK cells via NKG2D receptor. Imatinib mesylate interferes with NK/leukemic targets.24 DC: Dendritic cell; IM: Imatinib Mesylate; IRF: Interferon regulatory factor; STAT-1: Signal Transducer and Activator of Transcription factor-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376977&req=5

Figure 2: Figure 2. Tumors parameters implicated in the activation of NK cells. In RCC, VHL mutations induce constitutive activation and accumulation of Hypoxia-inducible factor (HIF). Certain VHL mutations correlate with low HLA-I molecules expression via a partially HIF-dependent pathway. The low expression of HLA-I molecules by VHL-mutated RCC cells reduces the engagement of NKG2A inhibitory receptor, shifting the balance toward NK cell activation. Membrane HLA-G molecules upregulate inhibitory receptors (NKG2A,and ILT2) on NK cells. Membrane-bound IL15 (Mb-IL15) is involved in NK cell activation and survival. In CML, the oncogeneic protein bcr/abl induces the expression of ICAM-1 and NKG2D ligands on myeloid cells favoring NK/target conjugates and lysis. Altered IFNγ signaling in bcr/abl target maintains a low HLA-I molecules expression. Bcr/abl dendritic cells activate NK cells via NKG2D receptor. Imatinib mesylate interferes with NK/leukemic targets.24 DC: Dendritic cell; IM: Imatinib Mesylate; IRF: Interferon regulatory factor; STAT-1: Signal Transducer and Activator of Transcription factor-1.
Mentions: In RCC, we have shown that loss-of-function mutations of Von Hippel Lindau (VHL) gene may be targeted by NK cells (Fig. 2). This oncogenic event is important for the development of these tumors and 80% of RCC bear mutations in VHL gene leading to HIF (Hypoxia-inducible factor)-1 accumulation and increased activation of downstream signaling pathways.11,12 Previous studies including ours showed that NK cells lyse RCC cell lines and that LFA-1/ICAM-1 and HLA-I/NKR interactions are important in RCC recognition by NK cells.13-15 We have shown that certain loss-of-function VHL mutations correlate with a reduced expression of classical HLA-I molecules via a partially HIF-1α-dependent mechanism and with higher RCC lysis by NK cells.16 These results corroborate previous findings reporting that VHL controls the constitutive expression of STAT-1 and LMP2, involved in MHC-I dependent antigen presentation, probably via the downregulation of STRA-13.17 HLA-E molecules, ligands of the inhibitory receptor NKG2A, are also decreased in VHL-mutated cells. HLA-E promoter also contains STAT-1 binding site.18 HLA-I molecules are often downregulated in tumors and their modulation is considered a common mechanism of tumor escape from T cell immune response.19 Conversely, low HLA-I expression may shift the balance toward activation in NK cells. In non-tumor pathology and upon hypoxia-dependent HIF accumulation, the expression of MICA/B molecules, stress-induced ligands of the activating receptor NKG2D, was found augmented and correlated with increased NK cytotoxicity.20,21 In our studies, the expression of NKG2D ligands was not controlled by VHL mutation.

Bottom Line: The recent findings on NK activation indicate that these cells are important antitumor effectors.However, tumor-infiltrating NK cells are yet poorly characterized.We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin-INSERM U06; CNRS UMR 804; Université Paris Descartes; Paris, France.

ABSTRACT
The recent findings on NK activation indicate that these cells are important antitumor effectors. NK cells participate in the graft-vs.-leukemia effect to control the relapse in leukemic patients transplanted with allogeneic hematopoietic stem cells. In various tumors, correlation between NK cell infiltrates and prognosis were reported. However, tumor-infiltrating NK cells are yet poorly characterized. We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

No MeSH data available.


Related in: MedlinePlus